Multiple sclerosis (MS) is a degenerative and inflammatory neurological disease which affects the central nervous system, more specifically the myelin sheath. MS causes demyelination of nerve fibres resulting in short-circuiting of nerve impulses and thus a slowing or blocking of transmission along the nerve fibres, with associated disabling symptoms.
Alzheimer's disease is a major cause of dementia in the elderly. It may be described as a progressive pathological deterioration in personality, memory and intellect consistent with a generalised atrophy of corresponding brain centres. The emotional state, behaviour, cognitive function and thought processes of sufferers are all adversely affected. A minor disimprovement in memory which gradually becomes more apparent is the first indication of the onset of the disease.
The incidence of the condition is slightly less than 1% of the general population of the U.K. but rises to 5% in the over-65's and to 20% in the over-80's.
The biochemical basis and neuropathology of the disease are better understood than its aetiology. The possibility of a genetic link is being investigated, as are suggestions that aluminium is a causative factor.
Treatments available to date are of, at best, limited value and the progression of the disease is irreversible. Death normally occurs less than a decade after the illness first presents itself (Barker, S. and Branford, D.; Pharm. Journal Jan. 26, 1991, pp 116-118).
4-Aminopyridine (4-AP) has been found to improve the conduction of nerve impulses, thereby, alleviating symptoms in MS patients. 4-AP has been found to slow the potassium ion flow in nerve impulse transmission and, thereby, is effective in restoring conduction in blocked demyelinated nerves. In clinical trials carried out by Davis, F. A. and Stefoski, D. of The Rush Multiple Sclerosis Centre, U.S.A., 4-AP has been administered orally in multiple daily doses over 2-5 days to MS patients with mild to marked improvements being noted and minimal side effects.
3,4-Di-aminopyridine (3,4-DAP) has also been found to improve specific neurological deficits and visual evoked response latencies in MS patients when administered orally in multiple daily doses. Bever, C. T. JR; Leslie, J.; Camenga, D. L.; Panitch, H. S.; and Johnson, K. P., Ann. Neurol. 27(4), pp. 421-427 (Apr. 1990).
4-AP has also been found to improve the mental functions in patients with Alzheimer's disease. This effect is believed to be related to the potassium channel blocking action of 4-AP which in turn enhances calcium influx into the neuron thus prolonging nerve action potential and increasing transmitter release. Wesseling et al., N. Eng. J. of Med. 310(15), pp. 988-989 (Apr. 1984).
In the use of a drag for long-term therapy it is desirable that the drug be formulated so that it is suitable for once- or twice-daily administration to aid patient compliance. Further, in view of the nature of neurological diseases, it can be appreciated that there is a need for an improved dosage form. However, such a formulation must result in a controlled release of drug to the systemic circulation and therapeutically effective blood levels throughout a given treatment period.
Another problem with long-term therapy is the requirement of determining an optimum dose which can be tolerated by the patient. If such a dose is not determined this can lead to a diminution in the effectiveness of the drag being administered.
It is an object of the present invention to provide preparations suitable for the long-term administration of a mono- or di-aminopyridine active agent.
It is a further object of the present invention to provide the use of a mono- or di-aminopyridine active agent in a manner which enables one to achieve a tolerable state for said drug in a subject being treated therewith.